Dry-binders for tablets based on polyethylene glycol-polyvinyl alcohol graft polymers, the production and use thereof

Abstract

A finely divided binder in powder form consisting of a polyethylene glycol-polyvinyl alcohol graft polymer particles, wherein the particles have an average particle size D[4,3] in the range of from 10 to 70 μm.

Claims

1. A finely divided binder in powder form consisting of a polyethylene glycol-polyvinyl alcohol graft polymer particles, wherein the particles have an average particle size D[4,3] in the range of from 10 to 70 μm.

2. The finely divided binder according to claim 1, wherein the particles have an average particle size D[4,3] in the range of from 10 to 70 μm and a packing fraction k of 0.15 to 0.27, and where the binder is a dry-binder for pharmaceutical tablets.

3. The finely divided binder according to claim 1, wherein the graft copolymer has a polyvinyl alcohol content in the range of 75% b.w. and a polyethylene glycol units content in the range of 25% b.w.

4. The finely divided binder according to claim 1, wherein the average particle size D[4,3] is 10 to 60 μm.

5. The finely divided binder according to claim 1 wherein the average particle size D[4,3] is 15 to 50 μm.

6. The finely divided binder according to claim 1, containing a flowability agent.

7. The finely divided binder according to claim 1, consisting of a polyethylene glycol-polyvinyl alcohol graft polymer and 0.05 to 0.5% b.w., based on the graft polymer, of a flowability agent.

8. The finely divided binder according to claim 6, wherein the flowability agent is colloidal silica.

9. The process for producing a binder according to claim 1, which comprises adjusting the particle properties of polyethylene glycol-polyvinyl alcohol graft polymer particles to a volume weighted average particle size D[4,3] in the range of from 10 to 70 μm by milling or spray-drying.

10. The process for producing a binder according to claim 1, which comprises adjusting the particle properties of polyethylene glycol-polyvinyl alcohol graft polymer particles to a volume weighted average particle size D[4,3] in the range of from 10 to 70 μm and a packing fraction k of 0.15 to 0.27 by milling or spray-drying.

11. The process for producing a binder as claimed in claim 1, which comprises the steps of (i) providing an aqueous solution of a polyethylene glycol-polyvinyl alcohol graft polymer with a polymer solids content in the range of from 1 to 35% b.w., based on the aqueous solution, and (ii) spray drying by atomizing the solution into a spray apparatus.

12. The process for producing a spray-dried binder according to claim 11, which comprises the steps of heating the aqueous solution provided in step (i) to 50 to 180° C. prior to atomizing the heated solution.

13. The process according to claim 12 wherein the aqueous solution provided in step (i) is heated to 60 to 120° C. prior to atomizing the heated solution.

14. The process according to claim 9, wherein a flowability agent is injected into the spray apparatus.

15. The method of manufacturing solid pharmaceutical dosage forms using a finely divided binder in powder form according to claim 1, as a dry-binder for direct compression mixtures.

Description

EMBODIMENT 1

(1) A finely divided binder in powder form consisting of a polyethylene glycol-polyvinyl alcohol graft polymer particles, wherein the particles have an average particle size D[4,3] in the range of from 10 to 70 μm and a packing fraction k of 0.15 to 0.27, and.

EMBODIMENT 2

(2) A finely divided binder according to Embodiment 1, wherein the average particle size D[4,3] is 10 to 60 μm.

EMBODIMENT 3

(3) A finely divided binder according to Embodiment 1, wherein the average particle size D[4,3] is 15 to 50 μm.

EMBODIMENT 4

(4) A finely divided binder according to Embodiments 1 to 3, wherein the graft copolymer has a polyvinyl alcohol content in the range of 75% b.w. and a polyethylene glycol units content in the range of 25% b.w.

EMBODIMENT 5

(5) A finely divided binder according to any of the Embodiments 1 to 4, wherein the mean molecular weight (weight average) of the graft polymer lies in the range of from 15.000 to 50.000 g/mol.

EMBODIMENT 6

(6) A finely divided binder according to Embodiments 1 to 5, wherein the polyethylene glycol chain of the graft copolymer is a polyethylene glycol with an average molecular weight Mn 6000.

EMBODIMENT 7

(7) A finely divided binder according to any of Embodiments 1 to 6 containing a flowability agent.

EMBODIMENT 8

(8) A finely divided binder according to any of Embodiments 1 to 7, consisting of a polyethylene glycol-polyvinyl alcohol graft polymer and 0.05 to 0.5% b.w., based on the graft polymer, of a flowability agent.

EMBODIMENT 9

(9) A finely divided binder according to any of Embodiments 7 or 8, wherein the flowability agent is colloidal silica.

EMBODIMENT 10

(10) A finely divided binder according to any of Embodiments 1 to 8, containing a polyethylene glycol-polyvinyl alcohol graft polymer with a true density in the range of 1.03 g/ml+/−0.02 g/ml.

EMBODIMENT 11

(11) A process for producing a binder according to any of Embodiments 1 to 10, which comprises adjusting the particle properties of polyethylene glycol-polyvinyl alcohol graft polymer particles to a volume weighted average particle size D[4,3] in the range of from 10 to 70 μm and a packing fraction k of 0.15 to 0.27 by milling or spray-drying.

EMBODIMENT 12

(12) A process for producing a binder according to any of Embodiments 1 to 11, which comprises the steps of (i) providing an aqueous solution of a polyethylene glycol-polyvinyl alcohol graft polymer with a polymer solids content in the range of from 1 to 20% b.w., based on the aqueous solution, and (ii) atomizing the solution into a spray apparatus and drying of the atomized solution to a powder using a drying gas.

EMBODIMENT 13

(13) A process for producing a spray-dried binder according to Embodiment 12, which comprises the steps of heating the aqueous solution provided in step (i) to 50 to 180° C. prior to atomizing the heated solution.

EMBODIMENT 14

(14) A process according to Embodiments 12 and 13, wherein the aqueous solution provided in step (i) is heated to 60 to 120° C. prior to atomizing the heated solution.

EMBODIMENT 15

(15) A process according to any of Embodiments 12 to 14, wherein the aqueous solution provided in step (i) is heated to 70 to 110° C. prior to atomizing the heated solution.

EMBODIMENT 16

(16) A process according to any of Embodiments 12 to 15, wherein a flowability agent is injected into the spray apparatus.

EMBODIMENT 17

(17) A process according to any of Embodiments 12 to 16, wherein the polymer solids content of the spray solution is in the range of from 3 to 25% b.w.

EMBODIMENT 18

(18) A process according to any of Embodiments 12 to 16, wherein the polymer solids content of the spray solution is in the range of from 5 to 15% b.w.

EMBODIMENT 19

(19) A process according to any of Embodiments 12 to 18, wherein the polymer solids content of the spray solution is in the range of from 5 to 12.5% b.w.

EMBODIMENT 20

(20) A process according to any of Embodiments 12 to 19, wherein the atomization step (ii) is carried out using pressure nozzles.

EMBODIMENT 21

(21) A process according to any of Embodiments 12 to 19, wherein the atomization step (ii) is carried out using two-substance nozzles.

EMBODIMENT 22

(22) A process according to any of Embodiments 12 to 21, wherein the tower inlet temperature of the drying gas is in the range of from 100 to 200° C.

EMBODIMENT 24

(23) A process according to any of Embodiments 12 to 22, wherein the tower outlet temperature of the drying gas is in the range of from 50 to 120° C.

EMBODIMENT 25

(24) A process to any of Embodiments 11 to 24, wherein the particle size is further adjusted by a sieving step.

EMBODIMENT 26

(25) A method of manufacturing solid pharmaceutical dosage forms using a finely divided binder in powder form according to any of Embodiments 1 to 24, as a dry-binder for direct compression mixtures.

EMBODIMENT 27

(26) A method of manufacturing solid pharmaceutical dosage forms according to any of Embodiments 1 to 26 wherein the solid pharmaceutical dosage form is a tablet.

EMBODIMENT 28

(27) A method of manufacturing solid pharmaceutical dosage forms according to any of Embodiments 1 to 26 wherein the solid pharmaceutical dosage form is a roller compact.

EMBODIMENT 29

(28) A method of manufacturing solid pharmaceutical dosage forms according to any of Embodiments 1 to 27, wherein the resulting tablets show a hardness of 50 to 200 N.

EMBODIMENT 30

(29) A method of manufacturing solid pharmaceutical dosage forms using a finely divided dry binder in powder form according to any of Embodiments 1 to 27, as a dry-binder for direct compression mixtures, wherein the proportion of the dry-binder in the direct compression mixture is 5-15% b.w.

EXAMPLES

(30) Commercial Kollicoat® IR was used as a starting material with weight average molecular weight in the range of 20.000 g/mol (determined by SEC-MALLS, mobile phase: 0.08 mol/l TRIS-buffer pH 7 in water (+0.15 mol/L NaCl); stationary phase: TSK Gel; standard: pullulan; Detektor: DRI Agilent 1100)

(31) True density was measured at 23° C., according to EN ISO 1183-3 (gas pyknometer):

(32) Gas Pyknometer: Micromeritics, AccuPyc 1340; volume metering chamber 10 cm.sup.3; calibration with steel balls.

(33) Prior to the measurement the samples were dried overnight in a vacuum oven (Fa. Heraeus) at 23° C. and 5 hPa.

(34) Measurement was carried out at 23+/−0.1° C. and 1.35 MPa, using argon as measurement gas. Number of specimens tested: three (mass: 2.9782 g; 3.3450 g; 3.2190 g); Arithmetic mean density: 1.03030 g/ml; standard deviation+/−0.5%

(35) True density of the graft copolymer known as commercial Kollicoat® IR: 1.03 g/ml, true densities of the inventive products: 1.03 g/ml.

(36) Particle sizes: volume averaged particle sizes D[4,3] and the respective median d50 were measured using a Malvern Mastersizer 2000.

(37) Bulk densities were measured according to EN ISO 60 using a normed funnel.

(38) Tablet hardness was measured in accordance with Chapter 2.9.8. of the European Pharmacopeia 9 using a Sotax HT 100 tablet tester, the tablet hardness being determined successively on 20 tablets with a speed of the test jaw of 120 mm/min.

(39) Tablet Disintegration was measured according to Chapter 2.9.1. of the European Pharmacopeia 9, Test Method A.

(40) Spray Apparatus:

(41) Products A-D: Niro/Gea Spray Apparatus, Pressure nozzle, diameter 1.2 mm

(42) Product E. Niro Minor, Two-substance nozzle, diameter 1.0 mm

(43) Commercial Kollicoat IR material was used to prepare aqueous solutions with a polymer content of 5, 7.5, 10 and 12.5% bw. respectively.

(44) TABLE-US-00001 TABLE 1 Sprayed product % b.w. of polymer No. in spray solution A 5 B 7.5 C 10 D 12.5 E 10
Products A-D:

(45) The aqueous solutions were heated to 80° C. and atomized via three nozzles with a pressure of 20 MPa. The throughput of the spray solution was in the range of 800 kg/h. The inlet temperature of the drying gas (air) was 115° C., the outlet temperature 60° C.

(46) Product E: The particle characteristics of the resulting powders are listed in Table 2.

(47) Two-substance nozzle diameter 1.0 mm; Inlet air: 120° C.; outlet air 65° C.; feed rate 17 g/min; nozzle pressure: 0.4 MPa

(48) TABLE-US-00002 TABLE 2 Powder particle characteristics Spray product D [4, 3] d50 Bulk density Packing Angle of No. [μm] [μm] [g/I] fraction k Repose [°] A 36 33 200-220 0.194-0.214 20-25 B 49 45 198-218 0.192-0.212 20-25 C 59 54 214-222 0.208-0.216 20-25 D 66 60 240-254 0.233-0.247 20-25 E 10 6 190-220 0.184-0.214 20-25 A; sieved 23 22 190-210 0.184-0.204 20-25 Comparative 120 106 310 0.301 20-25 Ex. Kollicoat IR Kollicoat IR, 17 15 nd nd nd milled

Tableting Experiments

(49) TABLE-US-00003 TABLE 3 Direct compression mixtures with inventive binders No. Dicafos Kollidon CL_F Mg stearate Inventive DCM [% b.w.] [% b.w.] [% b.w.] binder [% b.w.] 1 94.5 2.5 0.5 2.5 2 92.0 2.5 0.5 5 3 89.5 2.5 0.5 7.5 4 87.0 2.5 0.5 10 5 82.0 2.5 0.5 15 6 77.0 2.5 0.5 20

(50) Dicafos A60: direct compressible anhydrous dicalcium phosphate, bulk density 1300-1400 g/l, Chemische Fabrik Budenheim

(51) Kollidon® CL-F: Crospovidone, BASF SE, bulk density 0.18-0.28 g/ml; Particle size sieve fraction: more than 95%<250 μm

(52) In addition, spray product A was sieved to a median particle size d50 of 22 μm. and used for the tableting experiments described below.

(53) Also, Kollicoat IR powder was milled to the particle size listed in Table 2 and used in a tableting mixture. Milling was carried out using a countercurrent fluidized bed mill AFG 100 (Alpine). Mill settings: 3 nozzles of 1.9 mm diameter; grinding gas pressure of 0.6 Pa; gas throughput 55.0 m.sup.3/h; 50 mm diameter deflector wheel; rotational speed 8000 rpm; 21 m/s tip speed; 0.7 kg/h product throughput, trial time 20 min; amount of ground product: 5 kg

(54) For Comparison: Direct Compression Mixtures without Inventive Binder:

Comparative Ex. I

(55) Dicafos A60 97.0%

(56) Kollidon Cl—F 2.5%

(57) Mg-stearate 0.5%

Comparative Ex. II

(58) Dicafos A60 87.0%

(59) Kollidon Cl—F 2.5%

(60) Mg-stearate 0.5%

(61) Kollicoat® IR 10%

(62) The direct compression mixtures were pressed to tablet under the following conditions:

(63) The individual components were sieved through a 0.8 mm sieve and then blended in ab turbula mixer (T10B) for 8 min. After addition of magnesium stearate the powders were blended for a further 2 min. The resulting powder blends were compressed into tablets on a single punch press (EK0, Korsch) with a punch diameter of 10 mm (biplanar) applying 5, 7.5, 10, 12.5 and 15 kN, respectively.

(64) The tablets were tested for hardness as described above. The results are listed in Table 4.

(65) TABLE-US-00004 TABLE 4 DCM No./ Spray Tablet Hardness [N] at Product, Particle different compression forces [kN] Size Distr. 5 kN 7.5 kN 10 kN 12.5 kN 15 KN Comp. DCM I/ n/m n/m 9 13 17 0% DCM 1, Product  7 18 24 38 50 A, d50 = 33 μm DCM 2, Product 12 28 43 62 76 A, sieved, d50 = 22 μm DCM 2, Product 10 23 36 51 65 A, d50 = 33 μm DCM 3, Product 16 34 52 73 91 A, sieved, d50 = 22 μm DCM 3, Product 14 35 55 79 104 A, d50 = 33 μm DCM 4, Product 22 50 80 107 138 A sieved, d50 = 22 μm DCM 4, 15 41 68 82 109 Product A, d50 = 33 μm DCM 4, Product 14 38 60 90 114 B, d50 = 45 μm DCM 4, Product 22 47 62 71 92 C, d50 = 54 μm DCM 4, Product 17 36 62 97 125 D, d50 = 60 μm DCM, 5 Product 35 72 126 155 183 A, d50 = 33 μm DCM 6, Product 63 — 143 — 213 A, d50 = 33 μm DCM 4, Product 25 40 68 91 122 E, d50 = 6 μm Comp. Ex. II n/m n/m 8 26 37 d50 = 106 μm n/m : not measurable, due to insufficient stability DCM No./Spray Disintegration time [s] obtained at Product, Particle different compression forces [kN] Size Distr. 5 kN 7.5 kN 10 kN 12.5 kN 15 KN Comp. DCM I/ n/m n/m 2 3 2 0% DCM 1, Product 3 2 6 4 5 A, d50 = 33 μm DCM 2, Product 9 14 12 10 11 A, sieved, d50 = 22 μm DCM 2, Product 6 9 10 11 9 A, d50 = 33 μm DCM 3, Product 25 21 21 21 25 A, sieved, d50 = 22 μm DCM 3, Product 18 15 11 14 20 A, d50 = 33 μm DCM 4, Product A 56 52 83 127 228 sieved, d50 = 22 μm DCM 4, Product 20 25 21 23 40 A, d50 = 33 μm DCM 4, Product 16 17 14 18 23 B, d50 = 45 μm DCM 4, Product 13 13 16 13 15 C, d50 = 54 μm DCM 4, Product 9 7 12 15 18 D, d50 = 60 μm DCM 4, Product E, 11 14 15 13 17 d50 = 58 μm DCM 5, Product 53 96 258 269 466 A, d50 = 33 μm DCM 6, Product 279 nd 600 nd 749 A, d50 = 33 μm DCM 4, Product 23 29 25 23 31 E, d50 = 6 μm DCM 4, Kollicoat 27 33 21 22 31 IR milled, d50 = 15 μm Comp. Ex. II/ nd nd 5 4 5 d50 = 106 μm Nd: not determined, tableting not possible